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Elucidating molecular events underlying the effects of arsenic and folate on DNA methylation

An emerging body of evidence suggests that arsenic (As) exposure leads to epigenetic dysregulation. Our team has previously demonstrated that chronic As exposure is associated with increased global DNA methylation. We hypothesize that the mechanism underlying this relates to As-induced alterations in post-translational histone modifications (PTHM). This work involves a cross-disciplinary collaboration with Max Costa at NYU that takes advantage of samples collected from our folate trial (FACT) to carry out a set of aims related to nutrition/environment/epigenetic interactions. We plan to characterize the influence of As exposure on histone modifications, relate changes in histone modifications to changes in DNA methylation, and characterize the impact of folic acid supplementation on these marks. Finally, using the Infinium Human Methylation450 array, we have identified a set of genes that are differentially methylated by As exposure and plan to determine gene-specific histone modifications at these loci. Joint lab meetings between the Costa lab at NYU and the Gamble lab at Columbia University will further foster our continued collaboration. Collectively, these aims will begin to elucidate the molecular events that underlie the effects of As and folate on DNA methylation.

We have made significant progress with our research. In our preliminary study of N=40 FACT study participants, we have found that total urinary As (uAs) was positively correlated with H3K9me2 (r = 0.36, P = 0.02) and inversely with H3K9ac (r = -0.47, P = 0.002). The associations between As and other PTHMs differed in a gender dependent manner. Follow-up work has evaluated gender specific effects of arsenic exposure on gene expression; this work is still in progress.

Our research team is continuing to analyze PTHMs in a much larger number of study participants from samples collected at multiple time points from our folic acid supplementation trial and to analyze plasma folate, B12, SAM, SAH and homocysteine levels in these same participants. We are also studying changes in gene expression in peripheral blood mononuclear cells from a subset of the FACT study participants as a function of As exposure. Gene expression is being assessed using Affymetrix gene chips and RT PCR. We are also studying the persistence of gene expression following removal of As exposure using cell culture systems. If gene expression alterations persist after removal of the As we will study epigenetic histone marks in the promoter of genes using CHIP.

These findings will contribute to the growing body of evidence linking As exposure to epigenetic dysregulation, which may play a role in the pathogenesis of As toxicity. Improving our scientific knowledge in the field of As- induced epigenetic dysregulation has tremendous implications for both preventive- and treatment-based approaches to reducing the burden of As-induced diseases. First, methyl donor status is readily amenable to manipulation by nutritional interventions. It is generally accepted that folate influences DNA methylation. However, it is not known if this effect is direct, or if it is mediated by an upstream effect on histone modifications. The latter may be more dynamic than changes in DNA methylation. Thus, folate and other modifiers of the methyl donor pool may represent simple, low cost, low-risk interventions for prevention of As-induced disease. Furthermore, gaining mechanistic insights of As-induced epigenetic dysregulation may lead to additional therapeutic approaches for As toxicity, as multiple components of the epigenetic machinery are targets for existing and emerging drug development. Currently, there are no proven effective interventions, preventive or therapeutic, that specifically target intermediates in the underlying pathways that may be common to As-induced disease. Such interventions are critically needed.